The present invention relates to bicyclic heterocycles of general formula 
the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, especially an inhibitory effect on signal transduction mediated by tyrosine kinases, the use thereof for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.
In the above general formula I
Ra denotes a hydrogen atom or a methyl group,
Rb denotes a phenyl, benzyl- or 1-phenylethyl group wherein the phenyl nucleus is substituted in each case by the groups R1 to R3, while
R1 and R2, which may be identical or different, in each case denote a hydrogen, fluorine, chlorine, bromine or iodine atom,
a methyl, ethyl, hydroxy, methoxy, ethoxy, amino, cyano, vinyl or ethynyl group,
an aryl, aryloxy, arylmethyl or arylmethoxy group,
a methyl or methoxy group substituted by 1 to 3 fluorine atoms or
R1 together with R2, if they are bound to adjacent carbon atoms, denote a xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CH, xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94or xe2x80x94CHxe2x95x90Nxe2x80x94NH group and
R3 denotes a hydrogen, fluorine, chlorine or bromine atom,
Rc denotes a hydrogen atom or a methyl group,
X denotes a methyne group substituted by a cyano group or a nitrogen atom,
A denotes a 1,1- or 1,2-vinylene group which may be substituted in each case by one or two methyl groups or by a trifluoromethyl group,
an ethynylene group or
a 1,3-butadien-1,4-ylene group optionally substituted by a methyl or trifluoromethyl group,
B denotes an alkylene or xe2x80x94CO-alkylene group wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, while the linking of the xe2x80x94CO-alkylene group to the adjacent group A in each case must take place via the carbonyl group,
a xe2x80x94COxe2x80x94O-alkylene- or xe2x80x94COxe2x80x94NR4-alkylene group wherein the alkylene moiety in each case contains 1 to 4 carbon atoms, while the linking to the adjacent group A in each case must take place via the carbonyl group, wherein
R4 denotes a hydrogen atom or a methyl or ethyl group,
or a carbonyl group,
C denotes a 2-oxo-morpholin-4-yl group substituted by the group R5 or by the group R5 and a C1-4-alkyl group, while
R5 denotes a C3-4-alkyl, hydroxy-C1-4-alkyl, C1-4-alkoxy-C1-4-alkyl, di-(C1-4-alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-4-alkyl)-piperazino-C1-4-alkyl, C1-4-alkylsulphanyl-C1-4-alkyl, C1-4-alkylsulphinyl-C1-4-alkyl, C1-4-alkylsulphonyl-C1-4-alkyl, cyano-C1-4-alkyl, C1-4-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl, C1-4-alkyl-aminocarbonyl-C-14-alkyl, di-(C1-4-alkyl)aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl or a 4-(C1-4-alkyl)-piperazino-carbonyl-C1-4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups R5, where R5 is as hereinbefore defined and the two groups R5 may be identical or different,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94(CH2)m, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2xe2x80x94CH2, xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2CH2CH2xe2x80x94 bridge optionally substituted by one or two C1-2-alkyl groups, while
m denotes the number 2, 3, 4, 5 or 6 and
Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or C1-4-alkylimino group,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5 position together with a hydrogen atom in the 6 position is replaced by a xe2x80x94(CH2)n, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2-bridge, while
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which may be substituted by 1 to 4 C1-2-alkyl groups,
D denotes a xe2x80x94Oxe2x80x94C1-6-alkylene group, while the alkylene moiety is linked to the group E, or
an oxygen atom, while this may not be linked to a nitrogen atom of the group E, and
E denotes an amino group substituted by 2 C1-4-alkyl groups, wherein the alkyl groups may be identical or different and each alkyl moiety may be substituted from the 2 position by a C1-4-alkoxy or di-(C1-4-alkyl)-amino group or by a 4- to 7-membered alkyleneimino group, while in the abovementioned 6- to 7-membered alkyleneimino groups in each case a methylene group may be replaced in the 4 position by an oxygen or sulphur atom or by a sulphinyl, sulphonyl- or N-(C1-4-alkyl)-imino group,
a 4- to 7-membered alkyleneimino group optionally substituted by 1 to 4 methyl groups,
a 6- to 7-membered alkyleneimino group optionally substituted by 1 or 2 methyl groups, wherein in each case a methylene group in the 4 position is replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl- or N-(C1-4-alkyl)-imino group,
an imidazolyl group optionally substituted by 1 to 3 methyl groups,
a C5-7-cycloalkyl group, wherein a methylene group is replaced by an oxygen or sulphur atom or by a sulphinyl, sulphonyl or N-(C1-4-alkyl)-imino group, or
D together with E denotes a hydrogen atom,
a C1-6-alkoxy group optionally substituted from the 2 position by a hydroxy- or C1-4-alkoxy group,
a C3-7-cycloalkoxy- or C3-7-cycloalkyl-C1-4-alkoxy group,
or a group Rd, where
Rd denotes a C2-6-alkoxy group which is substituted from the 2 position by a C4-7-cycloalkoxy- or C3-7- cycloalkyl-C1-3-alkoxy group,
a C4-7-cycloalkoxy- or C3-7-cycloalkyl-C1-6-alkoxy group wherein the cycloalkyl moiety in each case is substituted by a C1-4-alkyl, C1-4-alkoxy, di-(C1-4-alkyl)-amino, pyrrolidino, piperidino, morpholino, piperazino, 4-(C1-2-alkyl)-piperazino, C1-4-alkoxy-C1-2-alkyl, di-(C1-4-alkyl)-amino-C1-2-alkyl, pyrrolidino-C1-2-alkyl, piperidino-C1-2-alkyl, morpholino-C1-2-alkyl, piperazino-C1-2-alkyl- or 4-(C1-2-alkyl)-piperazino-C1-2-alkyl group, while the abovementioned cycloalkyl moieties may additionally be substituted by a methyl or ethyl group,
while, unless otherwise stated, by the aryl moieties mentioned in the definition of the abovementioned groups is meant a phenyl group which may be mono- or disubstituted by R6, while the substituents may be identical or different and
R6denotes a fluorine, chlorine, bromine or iodine atom, a C1-2-alkyl, trifluoromethyl or C1-2-alkoxy group, or
two groups R6, if they are bound to adjacent carbon atoms, together represent a C3-4-alkylene, methylenedioxy or 1,3-butadien-1,4-ylene group.
Preferred compounds of the above general formula I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a benzyl or 1-phenylethyl group or a phenyl group substituted by the groups R1 and R2, while
R1 denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, trifluoromethyl, cyano or ethynyl group and
R2 denotes a hydrogen or fluorine atom,
Rc denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a C1-4-alkylene group,
C denotes a 2-oxo-morpholin-4-yl group substituted by the group R5 or by the group R5 and a C1-4-alkyl group, while
R5 denotes a C3-4-alkyl, C1-2-alkoxy-C1-4-alkyl, di-(C1-2-alkyl)-amino-C1-4-alkyl, pyrrolidino-C1-4-alkyl, piperidino-C1-4-alkyl, morpholino-C1-4-alkyl, 4-(C1-2-alkyl)-piperazino-C1-4-alkyl, C1-2-alkylsulphanyl-C1-4-alkyl, C1-2-alkylsulphinyl-C1-4-alkyl, C1-2-alkylsulphonyl-C1-4-alkyl, cyano-C1-4-alkyl, C1-2-alkoxycarbonyl-C1-4-alkyl, aminocarbonyl-C1-4-alkyl, C1-2-alkyl-aminocarbonyl-C1-4-alkyl, di-(C1-2-alkyl)-aminocarbonyl-C1-4-alkyl, pyrrolidinocarbonyl-C1-4-alkyl, piperidinocarbonyl-C1-4-alkyl, morpholinocarbonyl-C1-4-alkyl- or a 4-(C1-2-alkyl)-piperazinocarbonyl-C1-4-alkyl group,
a 2-oxo-morpholin-4-yl group substituted by two groups R5, while R5 is as hereinbefore defined and the two groups R5 may be identical or different,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94(CH2)m, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2CH2-bridge, while
m denotes the number 2, 3, 4 or 5 and
Y denotes an oxygen or sulphur atom, a sulphinyl, sulphonyl or C1-2-alkylimino group,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5 position together with a hydrogen atom in the 6 position is replaced by a xe2x80x94(CH2)n, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2, xe2x80x94CH2xe2x80x94Yxe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94Yxe2x80x94CH2-bridge, where
Y is as hereinbefore defined and
n denotes the number 2, 3 or 4,
or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which may be substituted by 1 or 2 methyl or ethyl groups,
D denotes a xe2x80x94Oxe2x80x94C1-4-alkylene group, while the alkylene moiety is linked to the group E, and
E denotes a dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, 4-methyl-piperazino- or 4-ethyl-piperazino group or
D together with E denotes a hydrogen atom,
a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylmethoxy or tetrahydropyranylmethoxy group,
a cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy group or
a group Rd, where
Rd denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-ethoxy, 2-(cyclopropylmethoxy)-ethoxy or 2-(cyclobutylmethoxy)-ethoxy group,
the tautomers, stereoisomers and salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a 1-phenylethyl, 3-methylphenyl, 3-chlorophenyl, 3-bromophenyl- or 3-chloro-4-fluorophenyl group,
Rc denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a methylene group,
C denotes a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl, diethylaminoethyl, cyanomethyl or cyanoethyl group,
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94CH2CH2, xe2x80x94CH2CH2CH2, xe2x80x94CH2CH2CH2CH2, xe2x80x94CH2CH2CH2CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2, xe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2CH2, xe2x80x94CH2xe2x80x94NC2H5xe2x80x94CH2CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2, xe2x80x94CH2CH2xe2x80x94NCH3xe2x80x94CH2CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94NC2H5xe2x80x94CH2CH2xe2x80x94 bridge,
a 2-oxo-morpholin-4-yl group, wherein a hydrogen atom in the 5 position together with a hydrogen atom in the 6 position is replaced by a xe2x80x94CH2CH2CH2, xe2x80x94CH2CH2CH2CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2, xe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2, xe2x80x94CH2xe2x80x94NC2H5xe2x80x94CH2, xe2x80x94CH2xe2x80x94Oxe2x80x94CH2CH2, xe2x80x94CH2xe2x80x94NCH3xe2x80x94CH2CH2, xe2x80x94CH2xe2x80x94NC2H5xe2x80x94CH2CH2, xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2, CH2CH2xe2x80x94NCH3xe2x80x94CH2xe2x80x94 or xe2x80x94CH2CH2xe2x80x94NC2H5xe2x80x94CH2xe2x80x94 bridge,
or, if D together with E denotes a group Rd, it may also denote a 2-oxo-morpholin-4-yl group which is substituted by 1 or 2 methyl groups, and
D together with E denotes a hydrogen atom,
a methoxy, ethoxy, 2-methoxy-ethoxy, 3-methoxy-propyloxy, tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy or tetrahydrofuranylmethoxy group,
a cyclobutyloxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy or cyclopentylmethoxy group or
a group Rd, where
Rd denotes a 2-(cyclobutyloxy)-ethoxy, 2-(cyclopentyloxy)-ethoxy, 2-(cyclopropylmethoxy)-ethoxy or 2-(cyclobutylmethoxy)-ethoxy group,
the tautomers, stereoisomers and salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
Ra denotes a hydrogen atom,
Rb denotes a 3-chloro-4-fluorophenyl group,
Rc denotes a hydrogen atom,
X denotes a nitrogen atom,
A denotes a 1,2-vinylene group,
B denotes a methylene group,
C denotes a 2-oxo-morpholin-4-yl group which is substituted by a methoxymethyl or methoxyethyl group, or
a 2-oxo-morpholin-4-yl group, wherein the two hydrogen atoms of a methylene group are replaced by a xe2x80x94CH2CH2xe2x80x94Oxe2x80x94CH2CH2xe2x80x94 bridge, and
D together with E denotes a hydrogen atom, a methoxy or cyclopropylmethoxy group,
the tautomers, stereoisomers and salts thereof.
The following particularly preferred compounds of the above general formula I are mentioned by way of example:
(1) 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline,
(2) 4-[(3-chloro-4-fluoro-phenyl)amino]-6- {[4-(2-oxo-1,9-dioxa-4-aza-spiro[5,5]undec-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline and
(3) 4-[(3-chloro-4-fluoro-phenyl)amino]-6-({4-[2-(2-methoxy-ethyl)-6-oxo-morpholin-4-yl]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline,
the tautomers, stereoisomers and salts thereof.
The compounds of general formula I may be prepared, for example, by the following methods:
reacting a compound of general formula 
optionally formed in a reaction mixture, wherein
Ra to Rc, A, B, D, E and X are as hereinbefore defined and
Z1, denotes a leaving group such as a halogen atom, e.g. a chlorine or bromine atom, or a hydroxy group,
with a compound of general formula
Hxe2x80x94C,xe2x80x83xe2x80x83(III)
wherein
C is as hereinbefore defined.
The reaction is optionally carried out in a solvent or mixture of solvents such as acetonitrile, methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane optionally in the presence of an inorganic or organic base and optionally in the presence of an activating agent, expediently at temperatures between xe2x88x9250 and 150xc2x0 C., preferably at temperatures between xe2x88x9220 and 100xc2x0 C.
With a compound of general formula II wherein Z1, denotes a leaving group, the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane conveniently in the presence of a tertiary organic base such as triethylamine or N-ethyl-diisopropylamine, wherein these organic bases may simultaneously serve as solvent, or in the presence of an inorganic base such as sodium carbonate or potassium carbonate, expediently at temperatures between xe2x88x9250 and 150xc2x0 C., preferably at temperatures between xe2x88x9220 and 100xc2x0 C.
With a compound of general formula II wherein Z1, denotes a hydroxy group, the reaction is preferably carried out in the presence of an activating agent, e.g. in the presence of thionyl chloride or phosphorus trichloride, conveniently in a solvent such as acetonitrile, methylene chloride, tetrahydrofuran, dioxane, toluene, chlorobenzene, ethylene glycol di-ethyl ether or sulpholane and optionally in the presence of a reaction accelerator such as sodium iodide at temperatures between xe2x88x9250 and 150xc2x0 C., but preferably at temperatures between xe2x88x9220 and 100xc2x0 C.
b) cyclising a compound of general formula 
optionally formed in a reaction mixture wherein
Ra to Rc, A, B, D, E and X are as hereinbefore defined and
Cxe2x80x2 denotes a correspondingly substituted N-(carboxymethyl)-N-(2-hydroxyethyl)-amino or N-(C1-4-alkyloxycarbonymethyl)-N-(2-hydroxyethyl)-amino group which can be converted into a C group by cyclisation.
The reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, acetonitrile, dimethylformamide, dimethylsulphoxide, sulpholane, benzene, toluene, chlorobenzene, tetrahydrofran, benzene/tetrahydrofuran or dioxane, expediently in the presence of an anhydrous acid such as trifluoroacetic acid, methanesulphonic acid or sulphuric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexyl carbodiimide, N,Nxe2x80x2-dicyclohexyl carbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
a protecting group for a carboxyl group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for an imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-diethoxybenzyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120xc2x0 C., preferably at temperatures between 10 and 100xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100xc2x0 C., but preferably at ambient temperatures between 20 and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoracetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120xc2x0 C. or by treating with sodium hydroxide solution, optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50xc2x0 C.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, cis/trans mixtures may be resolved into their cis and trans isomers, and compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
The compounds of general formulae II to IV used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (see Examples I to VII).
As already mentioned hereinbefore, the compounds of general formula I according to the invention and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible that the transmission of signals to components located further down is blocked.
The biological properties of the new compounds were investigated as follows:
The inhibition of EGF-R-mediated signal transmission can be demonstrated e.g. with cells which express human EGF-R and whose survival and proliferation depend on stimulation by EGF or TGF-alpha. A cell line of murine origin dependent on interleukin-3-(IL-3) which was genetically modified to express functional human EGF-R was used here. The proliferation of these cells known as F/L-HERc can therefore be stimulated either by murine IL-3 or by EGF (cf. von Rxc3xcden, T. et al. in EMBO J. 7, 2749-2756 (1988) and Pierce, J. H. et al. in Science 239, 628-631 (1988)).
The starting material used for the F/L-HERc cells was the cell line FDC-P1, the production of which has been described by Dexter, T. M. et al. in J. Exp. Med. 152, 1036-1047 (1980). Alternatively, however, other growth-factor-dependent cells may also be used (cf. for example Pierce, J. H. et al. in Science 239, 628-631 (1988), Shibuya, H. et al. in Cell 70, 57-67 (1992) and Alexander, W. S. et al. in EMBO J. 10, 3683-3691 (1991)). For expressing the human EGF-R cDNA (cf. Ullrich, A. et al. in Nature 309, 418-425 (1984)) recombinant retroviruses were used as described by von Ruden, T. et al., EMBO J. 7, 2749-2756 (1988), except that the retroviral vector LXSN (cf. Miller, A. D. et al. in BioTechniques 7, 980-990 (1989)) was used for the expression of the EGF-R cDNA and the line GP+E86 (cf. Markowitz, D. et al. in J. Virol. 62, 1120-1124 (1988)) was used as the packaging cell.
The test was performed as follows:
F/L-HERc cells were cultivated in RPML/1640 medium (BioWhittaker), supplemented with 10% foetal calf serum (FCS, Boehringer Mannheim), 2 mM glutamine (BioWhittaker), standard antibiotics and 20 ng/ml of human EGF (Promega), at 37xc2x0 C. and 5% CO2. In order to investigate the inhibitory activity of the compounds according to the invention, 1.5xc3x97104 cells per well were cultivated in triplicate in 96-well dishes in the above medium (200 xcexcl), the cell proliferation being stimulated with either EGF (20 ng/ml) or murine IL-3. The IL-3 used was obtained from culture supernatants of the cell line X63/0 mIL-3 (cf. Karasuyama, H. et al. in Eur. J. Immunol. 18, 97-104 (1988)). The compounds according to the invention were dissolved in 100% dimethylsulphoxide (DMSO) and added to the cultures in various dilutions, the maximum DMSO concentration being 1%. The cultures were incubated for 48 hours at 37xc2x0 C.
In order to determine the inhibitory activity of the compounds according to the invention the relative cell number was measured in O.D. units using the Cell Titer 96(trademark) Aqueous Non-Radioactive Cell Proliferation Assay (Promega). The relative cell number was calculated as a percentage of the control (F/LHERc cells without inhibitor) and the concentration of active substance which inhibits the proliferation of the cells by 50% (IC50) was derived therefrom. The following results were obtained:
The compounds of general formula I according to the invention thus inhibit the signal transduction by tyrosine kinases, as demonstrated by the example of the human EGF receptor, and are therefore useful for treating pathophysiological processes caused by hyperfunction of tyrosine kinases. These are e.g. benign or malignant tumours, particularly tumours of epithelial and neuroepithelial origin, metastasisation and the abnormal proliferation of vascular endothelial cells (neoangiogenesis).
The compounds according to the invention are also useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered production of mucus caused by stimulation of tyrosine kinases, e.g. in inflammatory diseases of the airways such as chronic bronchitis, chronic obstructive bronchitis, asthma, bronchiectasias, allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, xcex11-antitrypsin deficiency, or coughs, pulmonary emphysema, pulmonary fibrosis and hyperreactive airways.
The compounds are also suitable for treating diseases of the gastrointestinal tract and bile duct and gall bladder which are associated with disrupted activity of the tyrosine kinases, such as may be found e.g. in chronic inflammatory changes such as cholecystitis, Crohn""s disease, ulcerative colitis, and ulcers in the gastrointestinal tract or such as may occur in diseases of the gastrointestinal tract which are associated with increased secretions, such as Mxc3xa9nxc3xa9trier""s disease, secreting adenomas and protein loss syndrome,
also for treating nasal polyps and polyps of the gastrointestinal tract of various origins, such as for example villous or adenomatous polyps of the large bowel, but also polyps in familial polyposis coli, intestinal polyps in Gardner""s syndrome, polyps throughout the entire gastrointestinal tract in Peutz-Jeghers Syndrome, inflammatory pseudopolyps, juvenile polyps, colitis cystica profunda and pneumatosis cystoides intestinales.
Moreover, the compounds of general formula I and the physiologically acceptable salts thereof may be used to treat kidney diseases, particularly cystic changes as in cystic kidneys, for treating renal cysts which may be idiopathic in origin or which occur in syndromes such as e.g. tubercular sclerosis, in von-Hippel-Lindau Syndrome, in nephronophthisis and spongy kidney and other diseases caused by abnormal functioning of tyrosine kinases such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes, diseases of the immune system, hyperproliferation of haematopoietic cells, etc.
By reason of their biological properties the compounds according to the invention may be used on their own or in conjunction with other pharmacologically active compounds, for example in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastine), compounds which interact with nucleic acids (e.g. cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), antibodies, etc. For treating respiratory tract diseases, these compounds may be used on their own or in conjunction with other therapeutic agents for the airways, such as substances with a secretolytic, broncholytic and/or anti-inflammatory activity. For treating diseases in the region of the gastrointestinal tract, these compounds may also be administered on their own or in conjunction with substances having an effect on motility or secretion or with anti-inflammatory substances. These combinations may be administered either simultaneously or sequentially.
These compounds may be administered either on their own or in conjunction with other active substances by intravenous, subcutaneous, intramuscular, intrarectal, intraperitoneal or intranasal route, by inhalation or transdermally or orally, whilst aerosol formulations are particularly suitable for inhalation.
For pharmaceutical use the compounds according to the invention are generally used for warm-blooded vertebrates, particularly humans, in doses of 0.01-100 mg/kg of body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.
The following Examples are intended to illustrate the present invention without restricting it:
Preparation of the starting products: